WO2002009686A2 - Inhibiteurs de phosphatases cdc25 - Google Patents

Inhibiteurs de phosphatases cdc25 Download PDF

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Publication number
WO2002009686A2
WO2002009686A2 PCT/FR2001/002443 FR0102443W WO0209686A2 WO 2002009686 A2 WO2002009686 A2 WO 2002009686A2 FR 0102443 W FR0102443 W FR 0102443W WO 0209686 A2 WO0209686 A2 WO 0209686A2
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WO
WIPO (PCT)
Prior art keywords
radical
ethyl
amino
phenyl
dihydroxy
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PCT/FR2001/002443
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English (en)
French (fr)
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WO2002009686A3 (fr
Inventor
Grégoire Prevost
Marie-Christine Brezak Pannetier
Marie-Odile Galcera Contour
Christophe Thurieau
Françoise GOUBIN-GRAMATICA
Bernard Ducommun
Christophe Lanco
Original Assignee
Societe De Conseils De Recherches Et D'applications Scientifique (S.C.R.A.S.)
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Publication date
Priority to HU0303828A priority Critical patent/HUP0303828A3/hu
Priority to PL01365074A priority patent/PL365074A1/xx
Application filed by Societe De Conseils De Recherches Et D'applications Scientifique (S.C.R.A.S.) filed Critical Societe De Conseils De Recherches Et D'applications Scientifique (S.C.R.A.S.)
Priority to AU8223401A priority patent/AU8223401A/xx
Priority to EP01960837A priority patent/EP1370255A2/fr
Priority to US10/343,171 priority patent/US7196084B2/en
Priority to AU2001282234A priority patent/AU2001282234B2/en
Priority to BR0112824-8A priority patent/BR0112824A/pt
Priority to JP2002515239A priority patent/JP2004506618A/ja
Priority to KR10-2003-7001208A priority patent/KR20030020414A/ko
Priority to CA002417262A priority patent/CA2417262A1/fr
Priority to IL15399901A priority patent/IL153999A0/xx
Priority to MXPA03000860A priority patent/MXPA03000860A/es
Priority to NZ523739A priority patent/NZ523739A/en
Publication of WO2002009686A2 publication Critical patent/WO2002009686A2/fr
Priority to IL153999A priority patent/IL153999A/en
Priority to IS6701A priority patent/IS6701A/is
Priority to NO20030421A priority patent/NO20030421L/no
Publication of WO2002009686A3 publication Critical patent/WO2002009686A3/fr
Priority to HK04105845.2A priority patent/HK1063016A1/xx
Priority to US11/350,692 priority patent/US20060154933A1/en
Priority to US11/410,659 priority patent/US20060235027A1/en
Priority to AU2006233164A priority patent/AU2006233164B2/en

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Definitions

  • the subject of the present invention is new inhibitors of cdc25 phosphatases, and in particular of cdc25-C phosphatase.
  • kinases The transition between the different phases of the cell cycle during mitosis or meiosis is controlled by a set of proteins whose enzymatic activities are associated with different states of phosphorylation. These states are controlled by two main classes of enzymes: kinases and phosphatases.
  • cyclin-dependent kinases play a major role in this control of the cell cycle. Their activities are regulated by their molecular associations with other proteins called cyclins. In addition, endogenous inhibitors are able to prevent these activities.
  • endogenous inhibitors are able to prevent these activities.
  • inhibitors of this family of kinases have already been identified and studied in several therapeutic fields such as oncology to prevent the division of tumor cells (McDonald and el-Deiry, Int. J.
  • CDKs are controlled by two other families of enzymes which work in opposition (Jessus and Ozon, Prog. Cell Cycle Res. (1995), 1, 215-228).
  • the first groups kinases such as Weel and Mikl which deactivate CDKs by phosphorylating certain amino acids (Den Haese et al., Mol. Biol Cell (1995), 6, 371-385).
  • the second groups together phosphatases such as Cdc25 which activate CDKs by dephosphorylating the tyrosine and threonine residues of CDKs (Gould et al., Science (1990), 250, 1573-1576).
  • cyclin B is itself phosphorylated by the Cdc2 kinase (cdkl) with which it is associated (Borgne et al., J. Biol Chem. (1999), 274, 11977-11986).
  • cdc25-A a family of 3 genes, cdc25-A, cdc25-B and cdc25-C, code for the human cdc25 proteins.
  • variants from alternative splicing of the cdc25B gene have been identified: these are cdc25Bl, cdc25B2 and cdc25B3 (Baldin et al., Oncogene (1997), 14, 2485-2495).
  • the proteins encoded by these variants would be localized differently in the cell (Davezac et al., Oncogene (2000), 19, 2179-2185).
  • the activity of cdc25 is regulated by the kinases Cdc2 and Cdk2. But in the absence of the cdc2 kinase, the activity of cdc25 can be activated by other kinases (Izumi and Maller, Mol. Biol. Cell (1995), 6, 215-226). Among these, the protein chkl phosphorylates cdc25-C on a serine at position 216, which increases its affinity for a chaperone protein 14-3-3. This bond neutralizes cdc25-C and consequently maintains the cdkl enzyme in a phosphorylated and therefore inactive state, not allowing entry into mitosis.
  • the chaperone protein allows the complex to pass into the cytoplasm thanks to a protein motif for exporting the nucleus (Lopez-Girona et al., Nature (1999), 397, 172-175).
  • a chemical inhibitor of chkl allows a cell to continue its cell cycle despite the induction of DNA breakage. This aspect makes it possible to increase the effectiveness of certain cytotoxic compounds such as campthotecin (Jackson et al., Cancer Res. (2000), 60, 566-572).
  • - Lymphomas in circulating lymphocytes, the expressions of the cdc25-B1 and -B3 RNAs are detected by RT-PCR while the expressions of cdc25-A, -B2 and -C are very weak or not detectable.
  • the analysis of these genes in non-Hodgkin's lymphomas shows a strong expression of cdc25-A and -B2 in approximately 35% of the tumors.
  • the cdc25-B1 and -B3 variants are detected in all of the tumors analyzed.
  • the expression of cdc25-C remains very weak in all of the samples (Hernandez et al., Int. J.
  • Vitamin K3 also known as menadione, was the first selective cdc25 phosphatase inhibitor described (Ham et al., Bioorg. Med. Chem. Lett. (1998) 8, 2507-2510). Since then, other cdc25 inhibitors have been identified and have a micromolar inhibitory activity on recombinant enzymes. Among these products, we can note:
  • Some of the compounds from a Ugi library containing groups mimicking phosphates are non-competitive inhibitors of cdc25-A which do not act on the active site.
  • the most active compound has an IC 50 of 0.5 ⁇ M and the interaction site is being identified (Bergnes et al., Bioorg. Med.
  • A represents a free radical scavenger radical, for example a substituted phenyl radical
  • X and Y are linking chains, for example alkylene, alkylene carbon, carbonylalkylene radicals;
  • R represents H or alkyl
  • B represents a carbocyclic or heterocyclic aryl radical, and preferably the 2-thienyl radical.
  • the invention provides new inhibitors of cdc25, and in particular of cdc25-C, which correspond to the general formula (I) defined below. These compounds are capable of being used as medicaments, in particular in the treatment of the following diseases / disorders: • inhibition of tumor proliferation alone or in combination with other treatments;
  • the compounds of the present invention are also, because of their inhibitory properties for cdc25 phosphatases, capable of being used to inhibit the proliferation of microorganisms, in particular yeasts.
  • One of the advantages of these compounds is their low toxicity on healthy cells. The Applicant has therefore now surprisingly discovered that the compounds corresponding to the general formula (!
  • A represents a radical (Al)
  • R 1 , R 2 , R 3 , R 4 and R 5 represent hydrogen atoms and the other three are independently chosen from a hydrogen atom, a halogen atom and an alkyl, hydroxy or alkoxy radical , alkylcarbonyloxy, alkylthio or NR 6 R 7 , it being further understood that:
  • R 1 and one of R 2 and R 4 are independently chosen from a hydroxy, alkylcarbonyloxy and NR 6 R 7 radical,
  • R 2 and one of R 3 and R 5 are independently chosen from a hydroxy, alkylcarbonyloxy and NR 6 R 7 radical,
  • R 4 and one of R 3 and R 5 are independently chosen from a hydroxy, alkylcarbonyloxy and NR 6 R 7 radical, - or alternatively one of R 1 , R 3 and R 5 is chosen from a radical hydroxy, alkylcarbonyloxy and NR 6 R 7 , and the remainder BN (W) -XY is attached to the radical A by a nitrogen atom, R 6 and R 7 representing, independently whenever they occur, an atom of hydrogen or an alkyl radical or R 6 and R 7 forming together with the nitrogen atom a 4- to 7-membered heterocycle comprising from 1 to 2 heteroatoms, the links necessary to complete the heterocycle being chosen independently from the radicals -CR 8 R 9 -, -O-, -S- and -NR 10 -, R 8 and R 9 independently representing each time that they intervene a hydrogen atom or an alkyl, alkoxy radical, benzyloxycarbonylamino or dialkylamino, and R 10 independently representing each time that they interven
  • A represents a radical (A2)
  • R 11 and one of R 13 , R 14 and R 15 represent hydroxy radicals while the other radicals among R 13 , R 14 and R 15 as well as R 16 represent hydrogen atoms, - or else R 12 and R 16 represent hydroxy radicals while R n , R 13 , R 14 and R 15 represent hydrogen atoms;
  • B represents a radical -CO-, -NH-CO- (CH 2 ) n - or - (CH 2 ) p -, n being an integer from 0 to 3 and p being an integer from 0 to 1;
  • W represents a hydrogen atom or an alkyl radical
  • X represents a radical - (CH 2 ) q -, - (CH 2 ) q -NH- or -CO- (CH 2 ) r -, q being an integer from 1 to 6 and r an integer from 0 to 6;
  • R 17 and R 18 represent radicals chosen independently from a hydrogen atom and an alkyl radical;
  • R 19 represents a hydrogen atom, a halogen atom, a nitro, alkyl, alkylthio radical, NR 21 R 22 , -SO 2 -NR 23 R 24 , -NH-SO 2 -R 25 or -OP (O ) (OR 26 ) (OR 27 ), R 21 and R 22 independently representing a hydrogen atom or an alkyl radical, R 23 and R 24 independently representing a hydrogen atom or an alkyl radical, or alternatively R 23 and R 24 representing together with the nitrogen atom which carries them a heterocycle of 5 to 7 members whose complementary links are chosen independently from -CHR 28 -, -NR 29 -, -O- and -S-, R 28 and R 29 representing, independently each time they occur, a hydrogen atom or an alkyl radical,
  • R 25 representing an alkyl or haloalkyl radical or one of the aryl, heteroaryl, aralkyl or heteroaralkyl radicals in which the aryl or heteroaryl ring is optionally substituted by one or more radicals chosen independently from a halogen atom and alkyl, haloalkyl, hydroxy radicals, alkoxy or nitro, except for the possible nitrogen atoms of the heteroaryl ring for which the optional substituents are chosen from alkyl radicals,
  • R 26 and R 27 being independently chosen from alkyl radicals, and R 20 represents a hydrogen atom, a halogen atom or an alkyl, alkoxy or alkylthio radical, or alternatively Y represents the radical (T) represented below
  • R 20 represents a hydrogen atom or an alkyl, alkoxy or alkylthio radical, - when X represents a radical - (CH 2 ) q -NH- or when the set BN (W) -XY is such that it represents the radical
  • Y exclusively represents a radical -SO 2 -R 30 in which R 30 represents an alkyl, haloalkyl radical or one of the aryl, heteroaryl, aralkyl or heteroaralkyl radicals in which the aryl or heteroaryl ring is optionally substituted by one or more selected radicals independently from a halogen atom and alkyl, haloalkyl, hydroxy, alkoxy or nitro radicals, except for the possible nitrogen atoms of the heteroaryl ring for which the optional substituents are chosen from alkyl radicals;
  • B represents exclusively a radical -CO- or - (CH 2 ) -;
  • cdc25 phosphatase inhibitors and in particular cdc25-C phosphatase inhibitors, and can therefore be used to prepare a medicament intended to inhibit cdc25 phosphatases, and in particular cdc25-C phosphatase.
  • alkyl when no further details are given, is meant a linear or branched alkyl radical containing from 1 to 12 carbon atoms, preferably from 1 to 10 carbon atoms and more preferably from 1 to 6 carbon atoms .
  • alkenyl when it is not given more precision, is meant a linear or branched alkyl radical having from 1 to 6 carbon atoms and having at least one unsaturation (double bond).
  • alkynyl when no further details are given, is meant a linear or branched alkyl radical containing from 1 to 6 carbon atoms and having at least one double unsaturation (triple bond).
  • carbocyclic aryl or heterocyclic a carbocyclic or heterocyclic system is understood to comprise at least one aromatic ring, a system being said to be heterocyclic when at least one of the rings which composes it comprises a heteroatom (O, N or S); when a carbocyclic or heterocyclic aryl radical is said to be substituted without being given any further details, it is understood that said carbocyclic or heterocyclic aryl radical is substituted from 1 to 3 times, and preferably from 1 to 2 times, by different radicals a hydrogen atom which, if not specified, is chosen from a halogen atom and the alkyl or alkoxy radicals; moreover, when it is not given more precision, one understands by aryl an exclusively carbocyclic aryl.
  • haloalkyl is meant an alkyl radical in which at least one of the hydrogen atoms (and possibly all) is replaced by a halogen atom.
  • alkylthio, alkoxy, haloalkyl, haloalkoxy, aminoalkyl, alkenyl, alkynyl, aralkyl radicals are meant respectively the alkylthio, alkoxy, haloalkyl, haloalkoxy, aminoalkyl, alkenyl, alkynyl, aralkyl radicals whose alkyl radical has the meaning indicated above.
  • linear or branched alkyl having from 1 to 6 carbon atoms is meant in particular the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, pentyl, neopentyl, isopentyl, hexyl, isohexyl radicals.
  • carbocyclic aryl is meant in particular the phenyl and naphthyl radicals.
  • heterocyclic or heteroaryl aryl is meant in particular the thienyl, imidazolyl, thiazolyl, oxazolyl and pyridyl radicals.
  • halogen is meant the fluorine, chlorine, bromine or iodine atoms.
  • pharmaceutically acceptable salt is intended to mean in particular addition salts of inorganic acids such as hydrochloride, hydrobromide, iodhydrate, sulfate, phosphate, diphosphate and nitrate or of organic acids such as acetate, maleate, fumarate, tartrate, succinate, citrate , lactate, methanesulfonate, p-toluenesulfonate, pamoate and stearate. Also falling within the scope of the present invention, when they can be used, the salts formed from bases such as sodium or potassium hydroxide. For other examples of pharmaceutically acceptable salts, reference may be made to "Knows selection for basic drugs", Int. J. Pharm. (1986), 33, 201-217.
  • the compounds according to the present invention may contain asymmetric carbon atoms. Consequently, the compounds according to the present invention have two possible enantiomeric forms, that is to say the “R” and “S” configurations.
  • the present invention includes the two enantiomeric forms and all combinations of these forms, including the "RS” racemic mixtures. For the sake of simplicity, when no specific configuration is indicated in the structural formulas, it should be understood that the two enantiomeric forms and their mixtures are represented.
  • the compounds of general formula (I) according to the invention will include at least one of the following characteristics:
  • R 1 , R 2 , R 3 , R 4 and R 5 represent hydrogen atoms and the other three are independently chosen from a hydrogen atom, a halogen atom and an alkyl, alkylcarbonyloxy, hydroxy radical , alkoxy or NR 6 R 7 , it being further understood that: - or else R 1 and one of R 2 and R 4 are independently chosen from a hydroxy, alkylcarbonyloxy and NR 6 R 7 radical,
  • R 2 and one of R 3 and R 5 are independently chosen from a hydroxy, alkylcarbonyloxy and NR 6 R 7 radical,
  • R 4 and one of R 3 and R 5 are independently chosen from a hydroxy, alkylcarbonyloxy and NR 6 R 7 radical,
  • R 1 , R 3 and R 5 is independently chosen from a hydroxy, alkylcarbonyloxy and NR 6 R 7 radical, and the remainder BN (W) -XY is attached to the radical A by a nitrogen atom ,
  • R 6 and R 7 representing, independently each time they occur, a hydrogen atom or an alkyl radical or R 6 and R 7 forming together with the nitrogen atom a 5- to 7-membered heterocycle comprising of 1 with 2 heteroatoms, the links necessary to complete the heterocycle being chosen independently from the radicals -CR 8 R 9 -, -O-, -S- and -NR 10 -, R 8 and R 9 representing independently each time that they involve a hydrogen atom or an alkyl or alkoxy radical, and R 10 independently representing each time that it intervenes a hydrogen atom or an alkyl radical, or alternatively
  • R 11 and one of R 13 , R 14 and R 15 represent hydroxy radicals while the other radicals among R 13 , R 14 and R 15 as well as R 16 represent hydrogen atoms, - or else R 12 and R 16 represent hydroxy radicals while R 11 , R 13 , R 14 and R 15 represent hydrogen atoms;
  • B representing a radical -CO-, -NH-CO- (CH 2 ) n - or - (CH 2 ) p -, n being an integer from 0 to 2 and p being an integer from 0 to 1;
  • X representing a radical - (CH 2 ) q -, - (CH 2 ) q -NH- or -CO- (CH 2 ) r , q being an integer from 1 to 4 and r an integer from 0 to 5; or the BN (W) -XY set being such that it represents the radical
  • B is as defined in general formula (I)
  • t is an integer from 0 to 2
  • s is an integer from 0 to 1
  • R 17 and R 18 represent radicals chosen independently from a hydrogen atom and an alkyl radical
  • R 19 represents a hydrogen atom, a halogen atom, a nitro, alkyl, alkylthio radical, NR 21 R 22 , -SO 2 -NR 23 R 24 , -NH-SO 2 -R 25 or -OP (0 ) (OR 26 ) (OR 27 ),
  • R 21 and R 22 independently representing a hydrogen atom or an alkyl radical
  • R 23 and R 24 independently representing a hydrogen atom or an alkyl radical
  • R 23 and R 24 representing together with the nitrogen atom which carries them a heterocycle of 5 to 6 members whose complementary links are chosen independently from -CHR 28 -, -NR 29 -, -O- and -S-, R 28 and R 29 representing, independently each time they intervene, a hydrogen atom or an alkyl radical
  • R 25 representing an alkyl or aryl radical optionally substituted by one or more radicals chosen from a halogen atom and alkyl, haloalkyl, alkoxy or nitro radicals, except for the possible nitrogen atoms of the heteroaryl ring for which the optional substituents are chosen from alkyl radicals, R 26 and R 27 being independently chosen from alkyl radicals, and R 20 represents a hydrogen atom or an alkyl or alkoxy radical, or alternatively Y represents the radical of formula (T)
  • R 20 represents a hydrogen atom or an alkyl or alkoxy radical
  • Y representing a radical -SO 2 -R 30 in which R 30 represents an alkyl, haloalkyl radical or one of the aryl, heteroaryl, aralkyl or heteroaralkyl radicals in which the aryl or heteroaryl ring is optionally substituted by one or more radicals chosen independently from a halogen atom and alkyl, haloalkyl, alkoxy or nitro radicals, except for any nitrogen atoms in the nucleus heteroaryl for which the optional substituents are chosen from alkyl radicals.
  • the compounds of general formula (I) according to the invention will include at least one of the following characteristics:
  • R 1 , R 2 , R 3 , R 4 and R 5 represent hydrogen atoms and the other three are independently chosen from a hydrogen atom, a halogen atom and an alkyl, alkylcarbonyloxy, hydroxy radical , alkoxy or NR 6 R 7 , it being further understood that: - or else R 1 and one of R 2 and R 4 are independently chosen from a hydroxy, alkylcarbonyloxy and NR 6 R 7 radical,
  • R 2 and one of R 3 and R 5 are independently chosen from a hydroxy, alkylcarbonyloxy and NR 6 R 7 radical,
  • R 4 and one of R 3 and R 5 are independently chosen from a hydroxy, alkylcarbonyloxy and NR 6 R 7 radical,
  • R 1 , R 3 and R 5 is independently chosen from a hydroxy, alkylcarbonyloxy and NR 6 R 7 radical, and the remainder BN (W) -XY is attached to the radical A by a nitrogen atom ,
  • R 6 and R 7 representing, independently each time they occur, a hydrogen atom or an alkyl radical having 1 to 3 carbon atoms or R 6 and R 7 forming together with the nitrogen atom a heterocycle from 5 to 6 links comprising from 1 to 2 heteroatoms, the links necessary to complete the heterocycle being chosen independently from the radicals -CR 8 R 9 -, -O- and -NR 10 -, R 8 and R 9 independently representing each time a hydrogen atom or an alkyl or alkoxy radical is involved, and R 10 independently representing each time a hydrogen atom or an alkyl radical is involved, or A representing a radical (A2)
  • R 11 and R 15 represent hydroxy radicals while R 12 , R 13 , R 14 and R 16 represent hydrogen atoms,
  • R 12 and R 16 represent hydroxy radicals while R n , R 13 , R 14 and R 15 represent hydrogen atoms;
  • W representing a hydrogen atom or an ethyl or ethyl radical
  • X representing a radical - (CH 2 ) q -, - (CH 2 ) q -NH- or -CO- (CH 2 ) r , q being an integer from 1 to 3 and r an integer from 0 to 4; or the BN (W) -XY set being such that it represents the radical
  • R 17 and R 18 represent radicals independently chosen from a hydrogen atom and an alkyl radical containing from 1 to 3 carbon atoms;
  • R 19 represents a nitro radical, NR 21 R 22 , -SO 2 -NR 23 R 24 , -NH-SO 2 -R 25 or
  • R 21 and R 22 independently representing a hydrogen atom or an alkyl radical
  • R 23 and R 24 independently representing a hydrogen atom or an alkyl radical
  • R 23 and R 24 representing together with the nitrogen atom which carries them a heterocycle of 5 to 6 members whose complementary links are chosen independently among -CHR 28 -, -NR 29 -, -O- and -S-, R 28 and R 29 representing, independently each time they occur, a hydrogen atom or an alkyl radical
  • R 25 representing an alkyl or aryl radical optionally substituted by one or more radicals chosen from a halogen atom and alkyl, haloalkyl, alkoxy or nitro radicals, except for the possible nitrogen atoms of the heteroaryl ring for which the optional substituents are chosen from alkyl radicals,
  • R 26 and R 27 being independently chosen from alkyl radicals, and R 20 represents a hydrogen atom or an alkyl radical, or alternatively Y represents the radical of formula (T)
  • R 20 represents a hydrogen atom or an alkyl radical
  • Y representing a radical -SO 2 -R 30 in which R 30 represents an alkyl or haloalkyl radical or one of the aryl or aralkyl radicals in which the aryl ring is optionally substituted by one or more radicals chosen independently from a halogen atom and radicals alkyl, haloalkyle, alkoxy or nitro, except for the possible nitrogen atoms of the heteroaryl ring for which the optional substituents are chosen from alkyl radicals.
  • the compounds of general formula (I) according to the invention will include at least one of the following characteristics: A representing a radical (Al)
  • R 1 , R 2 , R 3 , R 4 and R 5 represent hydrogen atoms and the other three are independently chosen from a hydrogen atom, a halogen atom and an alkyl, acetoxy, hydroxy radical , methoxy or NR 6 R 7 , it being further understood that:
  • R 1 and one of R 2 and R 4 are independently chosen from a hydroxy, acetoxy and NR 6 R 7 radical,
  • R 2 and one of R 3 and R 5 are independently chosen from a hydroxy, acetoxy and NR 6 R 7 radical, - or else R 4 and one of R 3 and R 5 are independently chosen from a hydroxy, acetoxy and NR 6 R 7 radicals,
  • R 1 , R 3 and R 5 is independently chosen from a hydroxy, acetoxy and NR 6 R 7 radical, and the remainder BN (W) -XY is attached to the radical A by a nitrogen atom , R 6 and R 7 representing, independently each time they occur, a hydrogen atom or an alkyl radical having 1 to 3 carbon atoms (this alkyl radical preferably being the methyl radical) or R 6 and R 7 forming together with the nitrogen atom a heterocycle having 6 links and comprising from 1 to 2 heteroatoms, the links necessary to complete the heterocycle being chosen independently from the radicals -CR 8 R 9 -, -O- and -NR 10 -, R 8 and R 9 independently representing each time they intervene a hydrogen atom or an alkyl radical (this alkyl radical preferably being the methyl radical), and R 10 independently representing each time that it intervenes a hydrogen atom or an alkyl radical (this alkyl radical being of p reference the methyl radical), or alternatively A
  • R and R represent hydroxy radicals while R, R, R and R 16 represent hydrogen atoms;
  • W representing a hydrogen atom or a methyl radical
  • X representing a radical - (CH 2 ) q -, - (CH 2 ) q -NH- or -CO- (CH 2 ) r , q being an integer from 1 to 3 and r an integer from 0 to 4; or the BN (W) -XY set being such that it represents the radical
  • B is as defined in general formula (I)
  • t is an integer from 0 to 2
  • s is an integer from 0 to 1
  • R 17 and R 18 represent radicals chosen independently from a hydrogen atom and a methyl radical
  • R 19 represents a nitro radical, NR 21 R 22 , -SO 2 -NR 23 R 24 , -NH-SO 2 -R 25 or
  • R 21 and R 22 independently representing a hydrogen atom or an alkyl radical
  • R 23 and R 24 independently representing a hydrogen atom or an alkyl radical, or else R 23 and R 24 representing together with the nitrogen atom which carries them a heterocycle of 5 to 6 members whose complementary links are chosen independently among -CHR 28 -, -NR 29 -, -O- and -S-, R 28 and R 29 representing, independently each time they intervene, a hydrogen atom or an alkyl radical,
  • R 25 representing an alkyl or aryl radical optionally substituted by one or more radicals chosen from a halogen atom and alkyl, haloalkyl, alkoxy or nitro radicals, except for the possible nitrogen atoms of the heteroaryl ring for which the optional substituents are chosen from alkyl radicals, R 26 and R 27 being independently chosen from alkyl radicals, and R 20 represents a hydrogen atom or a methyl radical (and preferably a hydrogen atom), or alternatively Y represents the radical of formula ( T)
  • R 20 represents a hydrogen atom or a methyl radical (and preferably a hydrogen atom);
  • Y representing a radical -SO 2 -R 30 in which R 30 represents an alkyl radical or one of the aryl or aralkyl radicals the aryl ring of which is optionally substituted by one or more radicals chosen independently from a halogen atom and alkyl radicals, haloalkyl, alkoxy or nitro, except for the possible nitrogen atoms of the heteroaryl ring for which the optional substituents are methyl radicals.
  • R 30 represents an alkyl radical or one of the aryl or aralkyl radicals the aryl ring of which is optionally substituted by one or more radicals chosen independently from a halogen atom and alkyl radicals, haloalkyl, alkoxy or nitro, except for the possible nitrogen atoms of the heteroaryl ring for which the optional substituents are methyl radicals.
  • the compounds of general formula (I) will be used to prepare a medicament intended to treat a disease chosen from the following diseases: proliferative tumor diseases, and in particular cancer, proliferative diseases non-tumor, parasitic diseases, viral infections, spontaneous alopecia, alopecia induced by exogenous products and radiation-induced alopecia.
  • a disease chosen from the following diseases: proliferative tumor diseases, and in particular cancer, proliferative diseases non-tumor, parasitic diseases, viral infections, spontaneous alopecia, alopecia induced by exogenous products and radiation-induced alopecia.
  • the compounds of general formula (I) used to prepare a medicament intended to treat proliferative diseases, parasitic diseases and viral infections will be such that the radical Y does not represent the radical of formula (T).
  • the compounds of general formula (I) in which the radical Y represents the radical of formula (T) will therefore preferably be used to prepare a medicament intended for treating spontaneous alopecia, alopecia induced by exogenous products and alopecia radiation-induced.
  • the compounds of general formula (I) may be used to prepare a medicament intended to treat cancer, and in particular breast cancer, lymphomas, neck and head cancers, lung cancer, cancer colon cancer, prostate cancer and pancreatic cancer.
  • the compounds of general formula (I) as defined above can be used to prepare a medicament intended to treat spontaneous alopecia, alopecia induced by exogenous products or alopecia radiation-induced.
  • the present invention also provides, as medicaments, the compounds of general formula (II)
  • A represents a radical (Al)
  • R 1 , R 2 , R 3 , R 4 and R 5 represent hydrogen atoms and the other three are independently chosen from a hydrogen atom, a halogen atom and an alkyl, hydroxy or alkoxy radical , alkylcarbonyloxy, alkylthio or NR 6 R 7 , it being further understood that: - or else R 1 and one of R 2 and R 4 are independently chosen from a hydroxy radical, alkylcarbonyloxy and NR 6 R 7 ,
  • R 2 and one of R 3 and R 5 are independently chosen from a hydroxy, alkylcarbonyloxy and NR 6 R 7 radical,
  • R 4 and one of R 3 and R 5 are independently chosen from a hydroxy, alkylcarbonyloxy and NR 6 R 7 radical,
  • R 1 , R 3 and R 5 are chosen from a hydroxy, alkylcarbonyloxy and NR 6 R 7 radical, and the residue BN (W) -XY is attached to the radical A by a nitrogen atom,
  • R 6 and R 7 representing, independently each time they occur, a hydrogen atom or an alkyl radical or R 6 and R 7 forming together with the nitrogen atom a heterocycle of 4 to 7 members comprising 1 with 2 heteroatoms, the links necessary to complete the heterocycle being chosen independently from the radicals -CR 8 R 9 -, -O-, -S- and -NR 10 -, R 8 and R 9 representing independently each time that they involve a hydrogen atom or an alkyl, alkoxy, benzyloxycarbonylamino or dialkylamino radical, and R 10 independently representing each time that it intervenes a hydrogen atom or an alkyl radical,
  • A represents a radical (A2)
  • R 11 and one of R 13 , R 14 and R 15 represent hydroxy radicals while the other radicals among R 13 , R 14 and R 15 as well as R 16 represent hydrogen atoms,
  • R 12 and R 16 represent hydroxy radicals while R 11 , R 13 , R 14 and R 15 represent hydrogen atoms;
  • B represents a radical -CO-, -NH-CO- (CH 2 ) n - or - (CH 2 ) P -, n being an integer from 0 to 3 and p being an integer from 0 to 1;
  • W represents a hydrogen atom or an alkyl radical;
  • X represents a radical - (CH 2 ) q -, - (CH 2 ) q -NH- or -CO- (CH 2 ) r -, q being an integer from 1 to 6 and r an integer from 0 to 6;
  • R 17 and R 18 represent radicals chosen independently from a hydrogen atom and an alkyl radical
  • R 19 represents a hydrogen atom, a halogen atom, a nitro, alkyl, alkylthio radical, NR 21 R 22 , -SO 2 -NR 23 R 24 , -NH-SO 2 -R 25 or -OP (O ) (OR 26 ) (OR 27 ), R 21 and R 22 independently representing a hydrogen atom or an alkyl radical, R 23 and R 24 independently representing a hydrogen atom or an alkyl radical, or alternatively R 23 and R 24 representing together with the nitrogen atom which carries them a heterocycle of 5 to 7 members whose complementary links are chosen independently from -CHR 28 -, -NR 29 -, -O- and -S-, R 28 and R 29 representing, independently whenever they occur, a hydrogen atom or an alkyl radical, R 25 representing an alkyl, haloalkyl radical or one of the aryl, heteroaryl, aralkyl or heteroaralkyl radicals in which the aryl or heteroaryl radical
  • Y exclusively represents a radical -SO 2 -R 30 in which R 30 represents an alkyl, haloalkyl radical or one of the aryl, heteroaryl, aralkyl or heteroaralkyl radicals in which the aryl or heteroaryl ring is optionally substituted by one or more selected radicals independently from a halogen atom and alkyl, haloalkyl, hydroxy, alkoxy or nitro radicals, except for the possible nitrogen atoms of the heteroaryl ring for which the optional substituents are chosen from alkyl radicals;
  • B represents exclusively a radical -CO- or - (CH 2 ) -;
  • the invention relates, as medicaments, to the following compounds of general formula (II):
  • the invention also relates also, as a medicament, 5- (4 - ⁇ [((lE) -amino (2-thienyl) methylidene] amino ⁇ phenyl) - ⁇ - [2- (dimethylamino) phenyljpentanamide or one of its pharmaceutically acceptable salts.
  • the invention further relates to pharmaceutical compositions comprising, as active principle, at least one of the compounds of general formula (II) defined above or a pharmaceutically acceptable salt of such a compound, and preferably a compound chosen from the following compounds:
  • a pharmaceutical composition according to the invention will comprise 5- (4 - ⁇ [((lE) -amino (2-thienyl) methylidene] amino ⁇ phenyl) -
  • a pharmaceutical composition according to the invention will comprise, as active principle, a compound chosen from the following compounds:
  • composition according to the invention will comprise, as active principle, a compound chosen from the following compounds:
  • the invention further relates to the use of a compound of general formula (II) as defined above for preparing a medicament intended to treat a disease chosen from among the following diseases: proliferative tumor diseases, and in particular cancer, non-tumor proliferative diseases, parasitic diseases, viral infections, neurodegenerative diseases, myopathies, spontaneous alopecia, alopecia induced by exogenous products and radio-induced alopecia.
  • a disease chosen from among the following diseases: proliferative tumor diseases, and in particular cancer, non-tumor proliferative diseases, parasitic diseases, viral infections, neurodegenerative diseases, myopathies, spontaneous alopecia, alopecia induced by exogenous products and radio-induced alopecia.
  • the compounds of general formula (II) will be used to prepare a medicament intended to treat a disease chosen from the following diseases: proliferative tumor diseases, and in particular cancer, non-tumor proliferative diseases, parasitic diseases, viral infections, spontaneous alopecia, alopecia induced by exogenous products and radio-induced alopecia.
  • a disease chosen from the following diseases: proliferative tumor diseases, and in particular cancer, non-tumor proliferative diseases, parasitic diseases, viral infections, spontaneous alopecia, alopecia induced by exogenous products and radio-induced alopecia.
  • the compounds of general formula (II) may be used to prepare a medicament intended to treat cancer, and in particular breast cancer, lymphomas, neck and head cancers, lung cancer, cancer colon cancer, prostate cancer and pancreatic cancer.
  • the invention also relates, as new industrial products, to the compounds of general formula (III)
  • A represents a radical (Al)
  • R 1 , R 2 , R 3 , R 4 and R 5 represent hydrogen atoms and the other three are independently chosen from a hydrogen atom, a halogen atom and an alkyl, hydroxy or alkoxy radical , alkylcarbonyloxy, alkylthio or NR 6 R 7 , it being further understood that:
  • R 1 and one of R 2 and R 4 are independently chosen from a hydroxy, alkylcarbonyloxy and NR 6 R 7 radical,
  • R 2 and one of R 3 and R 5 are independently chosen from a hydroxy, alkylcarbonyloxy and NR 6 R 7 radical,
  • R 4 and one of R 3 and R 5 are independently chosen from a hydroxy, alkylcarbonyloxy and NR 6 R 7 radical,
  • R 1 , R 3 and R 5 are chosen from a hydroxy, alkylcarbonyloxy and NR 6 R 7 radical, and the residue BN (W) -XY is attached to the radical A by a nitrogen atom
  • R 6 and R 7 representing, independently each time they occur, a hydrogen atom or an alkyl radical or R 6 and R 7 forming together with the nitrogen atom a heterocycle of 4 to 7 members comprising 1 with 2 heteroatoms, the links necessary to complete the heterocycle being chosen independently from the radicals -CR 8 R 9 -, -O-, -S- and -NR 10 -, R 8 and R 9 representing independently each time that they involve a hydrogen atom or an alkyl, alkoxy, benzyloxycarbonylamino or dialkylamino radical, and R 10 independently representing each time that it intervenes a hydrogen atom or an alkyl radical, or A represents a radical (A2)
  • R 11 and one of R 13 , R 14 and R 15 represent hydroxy radicals while the other radicals among R 13 , R 14 and R 15 as well as R 16 represent hydrogen atoms, - or else R 12 and R 16 represent hydroxy radicals while R 11 , R 13 , R 14 and R 15 represent hydrogen atoms;
  • B represents a radical -CO-, -NH-CO- (CH 2 ) n - or - (CH 2 ) P -, n being an integer from 0 to 3 and p being an integer from 0 to 1;
  • W represents a hydrogen atom or an alkyl radical
  • X represents a radical - (CH 2 ) q -, - (CH 2 ) q -NH- or -CO- (CH 2 ) r -, q being an integer from 1 to 6 and r an integer from 0 to 6;
  • R 17 and R 18 represent radicals chosen independently from a hydrogen atom and an alkyl radical;
  • R 19 represents a radical -SO 2 -NR 23 R 24 , -NH-SO 2 -R 25 or -OP (O) (OR 26 ) (OR 27 ), R 23 and R 24 independently representing an atom of hydrogen or an alkyl radical, or else R 23 and R 24 representing together with the nitrogen atom which carries them a heterocycle of 5 to 7 members whose complementary links are chosen independently from -CHR 28 -, -NR 29 -, -O- and -S-, R 28 and R 29 representing, independently each time they occur, a hydrogen atom or an alkyl radical, R 25 representing an alkyl, haloalkyl or one of the aryl radicals, heteroaryl, aralkyl or heteroaralkyl in which the aryl or heteroaryl nucleus is optionally substituted by one or more radicals chosen independently from a halogen atom and alkyl, haloalkyl, hydroxy, alkoxy or nitro radicals, except for any nitrogen atoms
  • R 26 and R 27 being independently selected from alkyl radicals, and R 20 represents a hydrogen atom, a halogen atom or an alkyl, alkoxy or alkylthio radical;
  • Y exclusively represents a radical -SO 2 -R 30 in which R 30 represents an alkyl, haloalkyl radical or one of the aryl, heteroaryl, aralkyl or heteroaralkyl radicals in which the aryl or heteroaryl ring is optionally substituted by one or more selected radicals independently from a halogen atom and alkyl, haloalkyl, hydroxy, alkoxy or nitro radicals, except for any nitrogen atoms in the nucleus heteroaryl for which the optional substituents are chosen from alkyl radicals;
  • B represents exclusively a radical -CO- or - (CH 2 ) -;
  • the invention also relates, as new products, to the following compounds of general formula (I):
  • the invention also relates, as a new industrial product corresponding to the general formula (T), 5- (4 - ⁇ [((lE) -amino (2-thienyl) methylidene] amino ⁇ phenyl) - ⁇ - [2 - (dimethylamino) phenyl] pentanamide.
  • the invention also relates to pharmaceutical compositions comprising, as active principle, a compound of general formula (III) or a pharmaceutically acceptable salt thereof.
  • Another subject of the invention is the use of compounds of general formula (III) or of pharmaceutically acceptable salts of the latter for preparing medicaments intended for treating a disease chosen from the following diseases: tumor proliferative diseases, and in particular cancer, non-tumor proliferative diseases, parasitic diseases, viral infections, neurodegenerative diseases, myopathies, spontaneous alopecia, alopecia induced by exogenous products and radio-induced alopecia.
  • a disease chosen from the following diseases: tumor proliferative diseases, and in particular cancer, non-tumor proliferative diseases, parasitic diseases, viral infections, neurodegenerative diseases, myopathies, spontaneous alopecia, alopecia induced by exogenous products and radio-induced alopecia.
  • the compounds of general formula (III) will be used to prepare a medicament intended to treat a disease chosen from the following diseases: proliferative tumor diseases, and in particular cancer, non-tumor proliferative diseases, parasitic diseases, viral infections, spontaneous alopecia, alopecia induced by exogenous products and radio-induced alopecia.
  • a disease chosen from the following diseases: proliferative tumor diseases, and in particular cancer, non-tumor proliferative diseases, parasitic diseases, viral infections, spontaneous alopecia, alopecia induced by exogenous products and radio-induced alopecia.
  • the compounds of general formula (111) may be used to prepare a medicament intended to treat cancer, and in particular breast cancer, lymphomas, neck and head cancers, lung cancer, cancer colon cancer, prostate cancer and pancreatic cancer.
  • the invention also relates to a process for the preparation of a compound of general formula (I) .3
  • (I) -2 with a compound of general formula R 25 -SO 2 Cl in an aprotic solvent (such as tetrahy ⁇ ⁇ ofuranne, dichloromethane or dimethylformamide) and in the presence of a base (such as pyridine, triethylamine or a supported base, for example morpholinomethyl-polystyrene resin; the base can possibly also serve as reaction solvent).
  • an aprotic solvent such as tetrahy ⁇ ⁇ ofuranne, dichloromethane or dimethylformamide
  • a base such as pyridine, triethylamine or a supported base, for example morpholinomethyl-polystyrene resin; the base can possibly also serve as reaction solvent.
  • the invention also relates to a process for the preparation of a compound of general formula (I).
  • aprotic solvent such as tetrahydrofuran, dichloromethane or dimethylformamide
  • a base such as pyridine, triethylamine or a supported base, for example morpholinomethyl-polystyrene resin; the base possibly being also used as reaction solvent.
  • the invention also relates to a process for the preparation of a compound of general formula (I).
  • aprotic solvent such as tetrahydrofuran, dichloromethane or dimethylformamide
  • a base such as pyridine, triethylamine or a supported base, for example mo holinomethyl-polystyrene resin; the base being capable of if necessary also serve as reaction solvent.
  • the invention also relates to a process for the preparation of a compound of general formula (I).
  • A-CO 2 H (V) in an aprotic solvent such as tetrahydrofuran, dichloromethane or dimethylformamide
  • a peptide coupling agent such as dicyclohexylcarbodiimide (DCC), l, l'-carbonyldiimidazole (CDI) ) or 1- (3-dimethylaminoproyl) -3-ethylcarbodiimide hydrochloride
  • the pharmaceutical composition can be in the form of a solid, for example powders, granules, tablets, capsules, liposomes or suppositories.
  • Suitable solid carriers can be, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, carboxymethyl cellulose sodium, polyvinylpyrrolidine and wax.
  • compositions containing a compound of the invention can also be presented in liquid form, for example, solutions, emulsions, suspensions or syrups.
  • suitable liquid carriers can be, for example, water, organic solvents such as glycerol or glycols, as well as their mixtures, in varying proportions, in water.
  • the administration of a medicament according to the invention can be done by topical, oral, parenteral route, by intramuscular injection, etc.
  • the administration dose envisaged for a medicament according to the invention is between 0.1 mg to 10 g depending on the type of active compound used.
  • the compounds of general formula (I) can be prepared for example by the methods described below.
  • Cas_mony . 1 [represents a substituted radiocalphenyl ⁇
  • the compounds of general formula (I) can be prepared from the nitrophenyl derivatives of general sub-formula (I). l according to the procedures shown in diagram 1 below.
  • the reduction of the nitro function can be carried out, for example, by heating the product in an appropriate solvent such as ethyl acetate with a little ethanol in the presence of SnCi 2 (J. Heterocyclic Chem.
  • the compounds of general formula (I) in which Y represents the alkylsulfonylaminophenyl radical can be easily prepared from the compounds of general formula (I) .2, scheme 1, according to conventional methods for the synthesis of sulfonamides, by the action of a sulfonyl halide on an amino derivative, in an aprotic solvent such as THF, dichloromethane or dimethylformamide (DMF), in the presence of a base such as pyridine, triethylamine or a supported base such as morpholinomethyl-polystyrene resin or even using pyridine as solvent.
  • aprotic solvent such as THF, dichloromethane or dimethylformamide (DMF)
  • a base such as pyridine, triethylamine or a supported base such as morpholinomethyl-polystyrene resin or even using pyridine as solvent.
  • the derivatives of the alkylaminophenyl or dialkylaminophenyl type can be obtained by mono- or dialkylation of the aminophenyl derivatives of sub-formula general (I) .2 according to conventional methods known to those skilled in the art.
  • Monoalkylation is carried out by reductive amination with an aldehyde or by nucleophilic substitution by reaction with an equivalent of haloalkyl R 21 -Hal to give the monoalkylated derivative of general sub-formula (I) .5.
  • a second alkylation can then be carried out if necessary by means of a haloalkyl R 22 -Hal to give the dialkylated derivative of general sub-formula (I). 6.
  • the nitrophenyl derivative of general sub-formula (I) .2 can be treated with adequate amounts of paraformaldehyde under a hydrogen atmosphere in a solvent such as ethanol and in the presence of a catalyst of the palladium on carbon type to give the dimethylaminophenyl derivative of general sub-formula ( ⁇ ) .6bis (cf. diagram 2 below).
  • the carboxamides of general formula (I), scheme 3, in which B represents -CO- and A, W, X, R 19 and R 20 are as defined above, are prepared by condensation of the acids of general formula (V), with the amines of general formula (IV) under the conventional conditions of peptide synthesis (M. Bodanszky, The Practice of Peptide Synthesis, 145 (Springer-Verlag, 1984)), for example in THF, dichloromethane or DMF in presence of a coupling reagent such as dicyclohexylcarbodiimide (DCC), l, l'-carbonyld ⁇ midazole (CDI) (J. Med. Chem.
  • DCC dicyclohexylcarbodiimide
  • CDI l, l'-carbonyld ⁇ midazole
  • the amines of general formula (I), scheme 4, in which B represents -CH 2 - and A, W, X, R J9 and R 20 are as defined above, are prepared by reaction of the aldehydes of general formula (VI) with amines of general formula (IV) in the middle reducer.
  • the reaction takes place in an alcoholic solvent such as, for example, methanol, and leads to the imine which is then converted to the amine by a reducing agent such as NaBH 4 or NaBH 3 CN or a borohydride resin Amberlite ® IRA 400 (Aldrich; 2.5 mmol BH 4 7 g of resin).
  • the amines of general formula (X) are obtained by condensation of the amines of general formula (VII) with acids of general formula (VIII) in which A, W and n are as defined above and Gp represents a group protecting the function amine such as, for example, a carbamate group, under the conventional conditions of peptide synthesis as described above.
  • the amino function is then deprotected (deprotection in an acid medium in the case where Gp represents a carbamate group such as, for example, the tert-butoxycarbonyl group).
  • amines of general formula (IV) in which X represents - (CH 2 ) q -, W represents H and R 19 represents a radical -SO 2 -NR 23 R 24 (hereinafter designated by amines of general formula ( IV) S ), can in particular be obtained in 6 stages according to methods of the literature, and in particular according to the method represented in diagram 8 below.
  • diagram 8 the alcohol of general formula (XXI) is obtained in 3 stages starting from the acid of general formula (XVffi), after passage to the sulfonamide by action of a primary or secondary amine on the chloride of sulfonyl under the conditions described above for the synthesis of sulfonamides, followed by an esterification, for example by treatment with trimethylsilyldiazomethane in an alcoholic solvent such as, for example, methanol, and a reduction of the ester function by a reducing agent such as LiBH 4 in a polar aprotic solvent such as, for example, THF.
  • an alcoholic solvent such as, for example, methanol
  • a reducing agent such as LiBH 4
  • a polar aprotic solvent such as, for example, THF.
  • the alcohol function is then halogenated by CBr 4 in the presence of triphenylphosphine, then converted to phthalimide by treatment with potassium phthalimidate in a polar solvent such as, for example, acetonitrile.
  • a polar solvent such as, for example, acetonitrile.
  • the amine of general formula (IV) S is obtained.
  • amines of general formula (IV) in which R 19 represents the group -OP (O) (OR 26 ) (OR 27 ) (hereinafter designated by amines of general formula (IV) p ) can be obtained in 2 steps according to methods of the literature, and in particular, when X represents a radical - (CH 2 ) q -, according to the method represented in diagram 9 below.
  • the phenol of general formula (XXIV) is substituted, scheme 9, using a phosphonate derivative, in particular the cyanophosphonate of general formula (XXV), in the presence of a base such as, for example, triethylamine in a solvent such as dichloromethane.
  • a base such as, for example, triethylamine
  • a solvent such as dichloromethane.
  • the protecting group for the amino function (Gp) of the compound of general formula (XXVI) is then cut under the appropriate conditions (for example in an acid medium in the case where Gp is a group of carbamate type, such as the tert-butoxycarbonyl group) to finally give the amine of general formula (IV) p .
  • Diagram 11 The non-commercial amines of general formula (XXVII) or (XXVII) ô s in which A, B, W, R 17 , R 18 , s, t and q are as defined above are obtained by the conventional methods by condensation carboxylic acids of general formula (V) and aldehydes of general formula (VI) on linear diamines of general formula (XXIX) or cyclic diamines of general formula (KXIX) bis, Scheme 11, according to methods analogous to those described more above and in which the protective group Gp of the amine can be a carbamate group such as the tert-butoxycarbonyl group.
  • the protective group is cut using known methods, such as, for example, cutting in a hydrochloric acid medium for the tert-butoxycarbonyl group.
  • the amines of general formula (XXVII), scheme 12, in which B represents - (CH 2 ) p - with p 0, X represents - (CH 2 ) q -, A, W and q are as defined above and Gp is a protecting group for an amino function (for example a protecting group of carbamate type such as the tert-butoxycarbonyl group), are prepared by reaction of the amines of general formula (XIV) with aldehydes of general formula (XXXI) under the conditions d reducing amination described above, or else by reaction of the same amines of general formula (XIV) with halogen derivatives of general formula (XXXII) according to conventional methods known to those skilled in the art, followed by a deprotection step of the intermediary of general formula (XXXIII) carried out under conditions conventional for a person skilled in the art.
  • X represents - (CH 2
  • - conditions III passage from an acetonitrile-water-trifluoroacetic acid mixture 50-950-0.2 (A) to an acetonitrile-water-trifluoroacetic acid mixture 900-100-0.2 (B) by a linear gradient over a 8.5 min period then elution with pure mixture B for 2 min.
  • - conditions IV passage from an acetonitrile-water-trifluoroacetic acid mixture 50-950-0.2 (A) to an acetonitrile-water-trifluoroacetic acid 950-50-0 (B) mixture by a linear gradient over a period of 8.5 min then elution with pure mixture B for 10.5 min.
  • Example 1 4- (dimethylammo) -2-methoxy ⁇ 6 - ( ⁇ methyl [2- (4-nitrophenyl) ethyl] - amino ⁇ methyl) phenol
  • reaction mixture is extracted with 2 times 50 ml of CH 2 C1 2 .
  • organic phase is washed with 10 ml of water, dried over sodium sulfate, filtered and concentrated in vacuo.
  • the residue is purified on a silica column (eluent: CH 2 Cl 2 / MeOH: 97/3).
  • the expected product is obtained in the form of a brown oil with a yield of 34% (0.34 g).
  • Example 4 hydrochloride of 3 - [(3 - ⁇ [amino (2-thienyl) methylidene] amino ⁇ - benzyl) amino] -N- [4- (dimethylamino) phenyl] propanamide
  • the evaporation residue is purified on a silica column (eluent: ethyl acetate / heptane: 2/1). 0.06 g (63% yield) of free base is obtained.
  • the hydrochloride is prepared by dissolving the 0.06 g (0.14 mmol) of base obtained previously in acetone (10 ml) and by adding 0.43 ml of a molar solution of hydrochloric acid in l 'anhydrous diethyl ether. The crystals obtained are filtered and rinsed with diethyl ether to give, after drying, 0.052 g of the desired product (yield of 74%) in the form of a beige solid. Melting point: 145-148 ° C.
  • Example 32 3 - ⁇ [4- (methylsulfonyl) piperazin-1-yl] carbonyl ⁇ naphthalene-2,6-diol
  • Example 33 3 - ⁇ [4- (butyIsulfonyl) piperazin-1-yl] carbonyl ⁇ naphthalene-2,6-diol
  • the phosphatase activity of the protein MBP-Cdc25C is evaluated by the dephosphorylation of 3-O-methylfluorescein phosphate (OMFP) to 3-O-methylfluorescein (OMF) with a determination of the fluorescence at 475 nm from the reaction product. This test makes it possible to identify inhibitors of the recombinant enzyme cdc25.
  • the preparation of the fusion protein MBP-cdc25C is described in PCT patent application WO 01/44467.
  • the reaction is carried out in 384-well plate format with a final volume of 50 ⁇ l.
  • the MBP-cdc25C protein (prepared as described above) is stored in the following elution buffer: 20 mM Tris-HCl pH 7.4; 250 mM NaCl; ImM EDTA; 1 mM DTT; 10 mM maltose. It is diluted to a concentration of 60 ⁇ M in the following reaction buffer: 50 mM Tris-HCl pH 8.2; 50 mM NaCl; 1 mM DTT; 20% glycerol.
  • the background noise measurement is carried out with the buffer without addition of the enzyme. The products are tested at decreasing concentrations from 80 ⁇ M.
  • the reaction is initiated by the addition of an OMFP solution at 500 ⁇ M final (prepared extemporaneously from a 12.5 mM stock solution in DMSO 100 % (Sigma # M2629)). After 4 hours at 30 ° C. in a 384-well disposable plate, the fluorescence measured at OD 475 nm is read using a Victor2 plate reader (EGG-Wallac). The determination of the concentration inhibiting the enzymatic reaction by 50% is calculated from three independent experiments. Only the values contained in the linear part of the sigmoid are used for the linear regression analysis.
  • the cells of the Mia PaCa2 line are seeded at the rate of 450,000 cells in a 10 cm petri dish in the modified Eagle medium from Dulbecco supplemented with 10% fetal calf serum. 48 hours later, the cells are treated for 1 hour with the test compound or menadione at 100 ⁇ M (reference inhibitor). The medium is renewed after washing in PB S.
  • the loading buffer concentrated 5 times (TrisHCl 125 mM pH 7.4; SDS 10%; glycerol 50%; bromophenol blue 0.025%; ⁇ -mercaptoethanol 7%) is added to the samples.
  • the samples are heated for 10 minutes at 100 ° C.
  • the samples are deposited in a volume of 40 ⁇ l on 12% Tris / Glycine gels (BioRad).
  • the migration takes place for 1 hour at 180 V.
  • the proteins are transferred to a nitrocellulose membrane (Hybond C, Amersham) under semi-dry conditions. The membrane is blocked for 1 hour in 5% milk (BioRad) with 0.1% Tween 20.
  • the membrane is incubated for 1 h 30 min with the secondary anti-rabbit immunoglobulin G antibody (anti-rabbit IgG-HRP, sc2030, Santa Cruz) diluted 1/40 000 th .
  • the proteins are revealed by electrochemiluminescence (western blotting detection system ECL + , Amersham) which is detected using photographic films (BioMax light, Sigma). The images are scanned (BioProfil scanner, Vilbert Lourmat) and processed under Powerpoint ® .
  • FIG. 1 represents the compared effect of menadione and of the compound of example 1 on the phosphorylation of cdc2 in the line Mia PaCa-2 (treatment of 3 hours with menadione or the compound of l 'example 1 and sampling 24 hours later).
  • the effect of a treatment on two human cell lines Mia-Paca2 and DU145 will be studied with the compounds of examples 1 to 5 described above.
  • the DU145 (human prostate cancer cells) and Mia-PaCa2 (human pancreatic cancer cells) cell lines were acquired from the American Tissue Culture Collection (Rockville, Maryland, USA).
  • the cells placed in 80 ⁇ l of modified Eagle medium from Dulbecco (Gibco-Brl, Cergy-Pontoise, France) supplemented with 10% fetal calf serum inactivated by heating
  • the compounds of Examples 1 to 4, 8 to 10, 13, 14, 16 to 18, 22 and 28 to 30 have an IC 50 less than or equal to 100 ⁇ M on the cell proliferation of the DU-145 lines.

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BR0112824-8A BR0112824A (pt) 2000-07-28 2001-07-26 Utilização de um composto ou de um sal farmaceuticamente aceitável do mesmo, medicamento, composto, composição farmacêutica, e, processo de preparação de um composto
CA002417262A CA2417262A1 (fr) 2000-07-28 2001-07-26 Inhibiteurs de phosphatases cdc25
AU8223401A AU8223401A (en) 2000-07-28 2001-07-26 Cdc25 phosphatase inhibitors
EP01960837A EP1370255A2 (fr) 2000-07-28 2001-07-26 Inhibiteurs de phosphatases cdc25
US10/343,171 US7196084B2 (en) 2000-07-28 2001-07-26 Cdc25 phosphatase inhibitors
AU2001282234A AU2001282234B2 (en) 2000-07-28 2001-07-26 CDC25 phosphatase inhibitors
PL01365074A PL365074A1 (en) 2000-07-28 2001-07-26 Cdc25 phosphatase inhibitors
JP2002515239A JP2004506618A (ja) 2000-07-28 2001-07-26 Ｃｄｃ２５ホスファターゼ阻害剤
MXPA03000860A MXPA03000860A (es) 2000-07-28 2001-07-26 Inhibidores de cdc25-fosfatasas.
HU0303828A HUP0303828A3 (en) 2000-07-28 2001-07-26 Cdc25 phosphatase inhibitors, process for their preparation and their use for preparation of pharmaceutical compositions
IL15399901A IL153999A0 (en) 2000-07-28 2001-07-26 Cdc25 phosphatase inhibitors
KR10-2003-7001208A KR20030020414A (ko) 2000-07-28 2001-07-26 Ｃｄｃ25 포스파타제 억제제
NZ523739A NZ523739A (en) 2000-07-28 2001-07-26 CDC25 phosphatase inhibitors
IL153999A IL153999A (en) 2000-07-28 2003-01-16 Preparations for inhibiting 5CDC 2 phosphatases, compounds for these preparations and methods for their preparation
NO20030421A NO20030421L (no) 2000-07-28 2003-01-27 Inhibitorer av Cdc25 fosfataser
IS6701A IS6701A (is) 2000-07-28 2003-01-27 Cdc25 fosfatasahemlar
HK04105845.2A HK1063016A1 (en) 2000-07-28 2004-08-06 Cdc25 phosphatase inhibitors
US11/350,692 US20060154933A1 (en) 2000-07-28 2006-02-09 Inhibitors of Cdc25 phosphatases
US11/410,659 US20060235027A1 (en) 2000-07-28 2006-04-25 Inhibitors of cdc25 phosphatases
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Publication number Priority date Publication date Assignee Title
FR2856688A1 (fr) * 2003-06-25 2004-12-31 Sod Conseils Rech Applic PRODUIT COMPRENANT AU MOINS UN INHIBITEUR DE PHOSPHATASE CDc25 EN ASSOCIATION AVEC AU MOINS UN AUTRE AGENT ANTI-CANCEREUX
JP2007514639A (ja) * 2003-06-25 2007-06-07 ソシエテ ド コンセイユ ド ルシェルシェ エ ダアップリカーション シャンティフィック（エス．セー．エール．アー．エス．） 少なくとも１の他の抗癌剤と組み合わせた少なくとも１のＣｄｃ２５ホスファターゼ阻害剤を含有する製品
EP2335702A1 (fr) * 2003-06-25 2011-06-22 Ipsen Pharma Produit comprenant au moins un inhibiteur de phosphatase Cdc25 en association avec au moins un autre agent anti-cancéreux
FR2915747A1 (fr) * 2007-05-04 2008-11-07 Sod Conseils Rech Applic Derives de tri-amino-pyrimidine comme inhibiteurs de phosphatase cdc25
WO2008152223A1 (fr) * 2007-05-04 2008-12-18 Ipsen Pharma S.A.S. Derives de tri-amino-pyrimidine comme inhibiteurs de phosphatase cdc25
US8288388B2 (en) 2008-07-17 2012-10-16 Convergence Pharmaceuticals Limited 3-pyridylcarbonyl-piperazinylsulfonyl derivatives
US8536183B2 (en) 2008-07-17 2013-09-17 Convergence Pharmaceuticals Limited 3-pyridylcarbonyl-piperazinylsulfonyl derivatives

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BR0112824A (pt) 2004-02-10
EP1602368A2 (fr) 2005-12-07
FR2812198A1 (fr) 2002-02-01
KR20030020414A (ko) 2003-03-08
RU2285521C2 (ru) 2006-10-20
US7196084B2 (en) 2007-03-27
PL365074A1 (en) 2004-12-27
CN100406449C (zh) 2008-07-30
AU2001282234B2 (en) 2006-07-27
US20040034103A1 (en) 2004-02-19
AU8223401A (en) 2002-02-13
HUP0303828A3 (en) 2007-10-29
EP1370255A2 (fr) 2003-12-17
AU2006233164B2 (en) 2008-10-23
HK1063016A1 (en) 2004-12-10
IL153999A (en) 2007-07-04
JP2004506618A (ja) 2004-03-04
US20060154933A1 (en) 2006-07-13
NO20030421D0 (no) 2003-01-27
FR2812198B1 (fr) 2008-07-18
NZ523739A (en) 2005-09-30
AU2006233164A1 (en) 2006-11-09
HUP0303828A2 (hu) 2004-03-01
US20060235027A1 (en) 2006-10-19
CA2417262A1 (fr) 2002-02-07
MXPA03000860A (es) 2003-06-06
CZ2003273A3 (cs) 2003-06-18
NO20030421L (no) 2003-03-19
IS6701A (is) 2003-01-27
CN1474689A (zh) 2004-02-11
EP1602368A3 (fr) 2009-09-02
IL153999A0 (en) 2003-07-31
WO2002009686A3 (fr) 2003-10-09

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